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Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14350-5. Epub 2005 Sep 22.

Expression of DNA polymerase {beta} cancer-associated variants in mouse cells results in cellular transformation.

Author information

1
Departments of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. joann.sweasy@yale.edu

Abstract

Thirty percent of the 189 tumors studied to date express DNA polymerase beta variants. One of these variants was identified in a prostate carcinoma and is altered from isoleucine to methionine at position 260, within the hydrophobic hinge region of the protein. Another variant was identified in a colon carcinoma and is altered at position 289 from lysine to methionine, within helix N of the protein. We have shown that the types of mutations induced by these cancer-associated variants are different from those induced by the wild-type enzyme. In this study, we show that expression of the I260M and K289M cancer-associated variants in mouse C127 cells results in a transformed phenotype in the great majority of cell clones tested, as assessed by focus formation and anchorage-independent growth. Strikingly, cellular transformation occurs after a variable number of passages in culture but, once established, does not require continuous expression of the polymerase beta variant proteins, implying that it has a mutational basis. Because DNA polymerase beta functions in base excision repair, our results suggest that mutations that arise during this process can lead to the onset or progression of cancer.

PMID:
16179390
PMCID:
PMC1242307
DOI:
10.1073/pnas.0505166102
[Indexed for MEDLINE]
Free PMC Article

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